Zuclopenthixol Other names: Zuclopentixol

Zuclopenthixol is a potent neuroleptic of the thioxanthene series with a piperazine side-chain. The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect. The thioxanthenes have a high affinity for both the adenylate cyclase coupled dopamine D₁ receptors and for the dopamine D₂ receptors; in the phenothiazine group the affinity for D₁ receptors is much lower than that for D₂ receptors, whereas butyrophenones, diphenylbutylpiperidines and benzamides only have affinity for D₂ receptors.

In the traditional tests for antipsychotic effect, e.g. antagonism of stereotypic behaviour induced by dopamine agonists, the chemical groups of neuroleptics mentioned reveal equal but dosage dependent activity. However, the antistereotypic effect of phenothiazines, butyrophenones, diphenylbutylpiperidines, and benzamindes is strongly counteracted by the anticholinergic drug, scopolamine, while the antisteriotypic effect of the thioxanthenes, e.g. zuclopenthixol, is not, or only very slightly, influenced by concomitant treatment with anticholinergics.

Zuclopenthixol given orally in man is relatively quickly absorbed and maximum serum concentrations are reached in 3-6 hours. There is good correlation between the dose of zuclopenthixol and the concentrations achieved in serum. The biological half-life in man is about one day.

Zuclopenthixol is distributed in the liver, lungs, intestines and kidney, with somewhat lower concentration in the brain. Small amounts of drug or metabolites cross the placenta and are excreted in milk.

Zuclopenthixol is metabolised by sulphoxidation, N-Dealkylation and glucuronic acid conjugation.

The faecal route of excretion predominates and mostly unchanged zuclopenthixol and N-dealkylated metabolite are excreted in this way.

After deep intramuscular injection of zuclopenthixol, serum levels of zuclopenthixol increase during the first week and decline slowly thereafter. A linear relationship has been observed between zuclopenthixol dosage and serum level. Metabolism proceeds by sulphoxidation, dealkylation and glucuronic acid conjugation. Sulphoxide metabolites are mainly excreted in the urine while unchanged drug and the dealkylated form tend to be excreted in the faeces.

Reproductive toxicity

Impaired mating performance and reduced conception rates were observed in rats treated with zuclopenthixol at doses equal to the maximum recommend human dose of 50 mg on a mg/m² basis.

There was no evidence of embryotoxicity or teratogenic effects in rats treated with zuclopenthixol, however adverse effects on pre-and postnatal development (i.e. increased stillbirths, reduced pup survival and delayed development of pups) was observed. The clinical significance of these findings is unclear and it is possible that the effect on pups was due to neglect from the dams that were exposed to doses of zuclopenthixol producing maternal toxicity.

Mutagenicity and carcinogenicity

Zuclopenthixol has no mutagenic potential. In a rat oncogenicity study, 30 mg/kg/day resulted in slight non statistical increases in the incidence of mammary adenocarcinomas and pancreatic islet cell adenomas and carcinomas in females of thyroid parafollicular carcinomas. This is a common finding for D₂ antagonists which increase prolactin secretion when administered to rats. The physiological differences between rats and humans suggest that these changes are not predictive of an oncogenic risk in patients.

Local toxicity

Local muscle damage is less pronounced with oily solutions of zuclopenthixol then with aqueous solutions of zuclopenthixol and other neuroleptics.